DOCSLIB.ORG

Combination of Raloxifene, Aspirin and Estrogen As Novel Paradigm of Hormone Replacement Therapy in Rabbit Model of Menopause

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Combination of Raloxifene, Aspirin and Estrogen As Novel Paradigm of Hormone Replacement Therapy in Rabbit Model of Menopause Acta Pharmacologica Sinica (2011) 32: 1031–1037 npg © 2011 CPS and SIMM All rights reserved 1671-4083/11 $32.00 www.nature.com/aps Original Article Combination of raloxifene, aspirin and estrogen as novel paradigm of hormone replacement therapy in rabbit model of menopause Fa-lin YANG1, #, Ke-qing HU2, #, Xin WANG3, #, Zi-mo LIU4, Qin HU4, Ji-fu LI4, Hong HE4, * 1Clinical Laboratory, Qilu Hospital, Shandong University, Ji-nan 250012, China; 2Department of Cardiology, Ji-nan Central Hospital Affiliated to Shandong University, Ji-nan 250012, China; 3Department of Internal Medicine, the Second Affiliated Hospital, Shan- dong University, Ji-nan 250012, China; 4Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry Of Health, and Department of Cardiology, Qilu Hospital, Shandong University, Ji-nan 250012, China Aim: To assess a novel hormone replacement therapy (HRT) paradigm using raloxifene, aspirin combined with estrogen in rabbit model of menopause. Methods: Female New Zealand white rabbits were ovariectomized or sham-operated. The ovariectomized rabbits were divided into 7 groups: estradiol valerate (E2), raloxifene, aspirin, E2 /raloxifene, E2/aspirin, E2 /raloxifene/aspirin and vehicle. Two weeks after the operation, the rabbits were administered the above drugs for 12 weeks. Then, the mammary glands were examined histologically, uterus was weighted, and blood sample was collected for analyzing the levels of estrogen, serum lipids and monocyte chemoattractant protein (MCP)-1, and platelet aggregation. The aortic tissue was examined morphometrically. -1 -1 -1 -1 Results: Compared with E2 0.1 mg·kg ·d treatment alone, the pairing of raloxifene 10 mg·kg ·d with E2 significantly decreased the extent of mammary gland branches and ducts (5.53%±1.23% vs 15.4%±2.17%, P<0.01), as well as the uterine weight (2.16±0.35 g vs 4.91±0.75 g, P<0.01). However, E2/raloxifene or E2 alone treatment significantly stimulated platelet aggregation relative to vehicle -1 -1 group. Addition of aspirin 5 mg·kg ·d reduced platelet aggregation to almost the same level as the vehicle group. E2 treatment exerted a positive effect on serum lipids and MCP-1, and a regression in aortic intimal plaque size compared to the vehicle. Raloxifene rein- forced the positive effects of E2. Conclusion: The combination of raloxifene, aspirin and E2 exhibits positive lipid, MCP-1 and atherosclerotic responses with minimal stimulation of breast and uterine tissues as well as platelet aggregation in a rabbit model of the menopause. Keywords: estrogen; raloxifene; aspirin; atherosclerosis; hormone replacement therapy Acta Pharmacologica Sinica (2011) 32: 1031–1037; doi: 10.1038/aps.2011.87; published online 18 Jul 2011 Introduction old assigned to estrogen therapy than in those assigned to pla- The beneficial effects of estrogen are well described and cebo[5]. However, estrogen therapy has also been reported to include reductions in low density lipoprotein cholesterol be linked with an increased risk of tissue-specific side effects, (LDL-C) and inflammatory cytokines, such as monocyte including uterine endometrial hyperplasia, which may result chemoattractant protein-1 (MCP-1), an increase in high den- in uterine cancer, and proliferative effects on mammary tissue, sity lipoprotein cholesterol (HDL-C), and enhanced vascular which may result in an increased risk of breast cancer[6, 7]. The function, amongst others[1–3]. In animal models, estrogen has ideal hormone replacement therapy (HRT) should reproduce been reported to reduce atherosclerosis[4] and a clinical study the beneficial effects of estrogen without producing these also demonstrated a lower calcified plaque burden in the coro- adverse responses. This concept has led to the development nary arteries of postmenopausal women aged 50 to 59 years of HRT with combined estrogen and progestin, with progestin serving to reverse the endometrial hyperplasia induced by estrogen. However, findings from randomized placebo-con- # These three authors contribute to the paper equally. * To whom correspondence should be addressed. trolled trials in postmenopausal women do not support any E-mail [email protected] cardiovascular benefits of estrogen plus progestin, and dem- Received 2011-01-01 Accepted 2011-05-19 onstrate an increase in the risk of breast cancer[8, 9]. Although npg www.nature.com/aps Yang FL et al 1032 the role of progestin remains poorly defined, preclinical and 2.25±0.20 kg) female New Zealand White rabbits (Agricul- clinical studies have suggested that the co-administration of tural Sciences Institute Products; Ji-nan, China) were used progestin may oppose the cardioprotective effects of estro- in the present study. The rabbits were housed individually gen[10–12]. Furthermore, progestin has no anti-estrogenic effect in standard rabbit cages with a room temperature of 20±2 ºC on mammary tissue and, as a result, women on combined and 12-h light cycle. After 2 weeks of acclimation, bilateral estrogen-progestin treatment had an increase in the relative ovariectomies were performed in 70 rabbits under general risk for breast cancer[8, 9]. anesthesia (sodium pentobarbital 30 mg/kg, intravenously). Continued efforts to provide efficacious HRT with improved All rabbits subsequently received a 1.5% cholesterol diet for safety and tolerability for postmenopausal women have gen- 12 weeks. The rabbits were randomized into seven groups erated interest in the development of selective estrogen recep- of 10 rabbits: (A) a placebo-control group receiving vehicle tor (ER) modulators (SERMs). Estrogen typically exhibits an control (saline: 2% Tween 80, 0.5% methylcellulose; OVX+Veh ER agonist effect in all tissues, whereas SERMs demonstrate group); (B) estradiol valerate (E2, Delpharm Lille SAS, Lys- -1 -1 mixed functional activity (ER agonist/antagonist) depending lez-Lannoy, France) 0.1 mg·kg ·d (OVX+E2 group); (C) ral- on the target tissue[13]. To date, no SERM alone has been able oxifene hydrochloride (Lilly SA, Madrid, Spain) 10 mg·kg-1·d-1 to achieve an ideal balance of ER agonist and antagonist activ- (OVX+Ral group); (D) aspirin (Huanghai Company, Shan- ity for an optimal postmenopausal therapy. However, it may dong, China) 5 mg·kg-1·d-1 (OVX+ASA group); (E) raloxifene be possible to achieve optimal results based on the blended paired with E2 (OVX+E2+Ral group); (F) aspirin paired with tissue-selective activities of a SERM and estrogen in a novel E2 (OVX+E2+ASA group); and (G) raloxifene and aspirin in approach. combination with E2 (OVX+E2+Ral+ASA group). Compounds The SERM chosen in this study to test our hypothesis was were administered orally in a saline vehicle to the rabbits. The -1 -1 raloxifene, as it has been confirmed to have estrogen agonist dose of E2 (0.1 mg·kg ·d ) selected was the dose commonly effects on lipids and estrogen antagonist effects on the breast used for research, which has been shown not to cause seri- and uterus[14, 15]. It is also the only SERM being specifically ous disorders in the major organs of cholesterol-fed rabbits[25]. studied for its effects on coronary heart disease events in a The dose of raloxifene (10 mg·kg-1·d-1) was chosen based on prospective randomized controlled trial, which demonstrated previous pharmacokinetic data that showed this dosage gen- that the incidence of coronary events was significantly lower erates a plasma raloxifene concentration comparable with that in postmenopausal women <60 years of age assigned to observed in clinical settings and which reduces aortic accu- raloxifene compared with those assigned to the placebo[16]. mulation of cholesterol in rabbits[26]. Furthermore, it has been Although raloxifene has been reported to be associated with reported that, at a dose of 10 mg·kg-1·d-1, raloxifene is able to [17, 18] -1 -1 an increased incidence of vasomotor symptoms , a previ- counteract the effects of 0.1 mg·kg ·d of E2 and maintain the ous study confirmed that combined use of 17β-estradiol with uterine weight at levels that are indistinguishable from those raloxifene was able to decrease the frequency of vasomotor of vehicle-treated controls in animal tests[27]. Aspirin was symptoms in comparison with raloxifene treatment alone[19]. used at an antithrombotic dosage (5 mg·kg-1·d-1). One group Based on these observations, the pairing of raloxifene with of 10 rabbits was sham-operated, and also received a 1.5% estrogen may represent an attractive therapeutic option. cholesterol diet but no hormone treatment (sham group). The However, estrogen has been reported to increase the risk study protocol was approved by the Animal Care Committee of venous thrombosis and arterial thrombotic events, such of Shandong University, China and was performed according as stroke[20–22]. Aspirin, one of the most widely used blood- to the Guidelines for the Use of Experimental Animals by the thinning agents in the world, is used long-term in low doses Ministry of Health, China. to prevent heart attacks, strokes and blood clot formation in At the end of study, the rabbits were sacrificed after 12 h people at high risk for these events. In animal tests, low-dose of fasting. Breast tissue specimens were fixed in 10% neutral aspirin has been shown to have a preventive effect on throm- buffered formalin, routinely processed, paraffin embedded, bus formulation[23] and in a clinical trial, it has been shown to sectioned and stained with hematoxylin and eosin. The per- prevent deep venous thrombosis and pulmonary embolism in centage of the extent of gland branches and ducts in the mam- patients postoperatively[24]. mary gland was determined using a computer-based quantita- Therefore, based on the available evidence, it may be postu- tive color image analysis system Ipp6.0 (Media Cybernetics, lated that combined use of raloxifene and aspirin with estro- Bethesda, MD, USA).
Load more

Recommended publications
  • Tamoxifen, Raloxifene Upheld for Prevention
    38 WOMEN’S HEALTH MAY 1, 2010 • FAMILY PRACTICE NEWS Tamoxifen, Raloxifene Upheld for Prevention BY KERRI WACHTER 9,736 on tamoxifen and 9,754 on ralox- 1.24, which was significant (P = .01). Both events) did not appear to be as effective ifene. The differences in numbers are due drugs reduced the risk of invasive breast as tamoxifen (57 events) in preventing WASHINGTON — Tamoxifen and to a combination of loss during follow- cancer by roughly 50% in the original re- noninvasive breast cancer (P = .052). raloxifene offer women at high risk of up or follow-up data becoming available port (median follow-up 47 months). “Now with additional follow-up, those developing breast cancer two effective for women who were lost to follow-up “We have estimated, however, that differences have narrowed,” he said. At options to prevent the disease, based on in the original report. Women on ta- this difference in the raloxifene-treated 8 years, there was no statistical signifi- 8 years of follow-up data for more than moxifen received 20 mg/day and those group represents 76% of tamoxifen’s cance between the two groups with a 19,000 women in the STAR trial. on raloxifene received 60 mg/day. chemopreventative benefit, which trans- risk ratio of 1.22 (P = .12). The relative While tamoxifen proved significantly At an average follow-up of 8 years, the lates into at 38% reduction in invasive risk of 1.22 favors tamoxifen, but ralox- more effective in preventing invasive breast relative risk of invasive breast cancer on breast cancers,” Dr.
    [Show full text]
  • A Guide to Feminizing Hormones – Estrogen
    1 | Feminizing Hormones ​ ​ A Guide to Feminizing Hormones Hormone therapy is an option that can help transgender and gender-diverse people feel more comfortable in their bodies. Like other medical treatments, there are benefits and risks. Knowing what to expect will help us work together to maximize the benefits and minimize the risks. What are hormones? Hormones are chemical messengers that tell the body’s cells how to function, ​ when to grow, when to divide, and when to die. They regulate many functions, including growth, sex drive, hunger, thirst, digestion, metabolism, fat burning & storage, blood sugar, cholesterol levels, and reproduction. What are sex hormones? Sex hormones regulate the development of sex characteristics, including the sex ​ organs such as genitals and ovaries/testicles. Sex hormones also affect the secondary sex characteristics that typically develop at puberty, like facial and body hair, bone growth, breast growth, and voice changes. There are three categories of sex hormones in the body: • Androgens: testosterone, dehydroepiandrosterone (DHEA), ​ dihydrotestosterone (DHT) • Estrogens: estradiol, estriol, estrone ​ • Progestin: progesterone ​ Generally, “males” tend to have higher androgen levels, and “females” tend to have higher levels of estrogens and progestogens. What is hormone therapy? Hormone therapy is taking medicine to change the levels of sex hormones in your body. Changing these levels will affect your hair growth, voice pitch, fat distribution, muscle mass, and other features associated with sex and gender. Feminizing hormone therapy can help make the body look and feel less “masculine” and more “feminine" — making your body more closely match your identity. What medicines are involved? There are different kinds of medicines used to change the levels of sex hormones in your body.
    [Show full text]
  • Structure and Origin of Uterine and Extragenital L=Ibroids Induced
    Structure and Origin of Uterine and Extragenital l=ibroids Induced Experimentally in the Guinea Pig by Prolonged Administration of Estrogens* Alexander Lipschotz, M.D., and Louis Vargas, Jr., M.D. (From Department o/ Experimental Medicine, National Health Service o/the Republic o/Chile, Santiago, Chile) (Received for publication December 13, x94o) The purpose of this communication is to present the These experimentally induced abdominal tumors findings of a detailed microscopical study of the sites present a smooth surface formed of a capsule com- of origin and stages of development of the subserous posed of flattened superficial cells (Plate 2, Figs. 2-A fibroid tumors induced in guinea pigs by prolonged and 2-B). The cells beneath the capsule resemble administration of estrogens. Details of treatment of fibroblasts. These cells have definite boundaries or the animals are given in the explanations of Plates I- 5. they are separated from each other by collagenous Subserous uterine tumors which can be induced in fibers (Plate 4, Fig. ix-C). guinea pigs by prolonged administration of estrogens, The masses of fibroid tumors arising from the apex as described by Nelson (26, 27), were found to be of the uterine horn may enclose the tubes or large fibroids. Lipschiitz, Iglesias, and Vargas (i3, 18, 22) tubal cysts. The demarcation between the muscular have shown that extragenital tumors in the abdominal coat of the tube and the tumor is not always sharp. cavity, induced by estrogens, also were fibroids. The In some instances, especially when the apical fibroid localization of these tumo~:s at various sites on the is small, the tumor is in close contact with an abun- uterus, pancreas, kidney, spleen, etc., have been de- dance of smooth muscle and adipose tissue (Plate 2, scribed by Iglesias (5), Vargas and Lipschiitz (32), Fig.
    [Show full text]
  • Effect of Tibolone on Bone Mineral Density in Postmenopausal Women: Systematic Review and Meta-Analysis
    Review Effect of Tibolone on Bone Mineral Density in Postmenopausal Women: Systematic Review and Meta‐Analysis Lizett Castrejón‐Delgado 1, Osvaldo D. Castelán‐Martínez 2, Patricia Clark 3, Juan Garduño‐Espinosa 4, Víctor Manuel Mendoza‐Núñez 1 and Martha A. Sánchez‐Rodríguez 1,* 1 Research Unit on Gerontology, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Mexico City 09230, Mexico; [email protected] (L.C‐D.); [email protected] (V.M.M.‐N.) 2 Clinical Pharmacology Laboratory, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Mexico City 09230, Mexico; [email protected] 3 Clinical Epidemiology Research Unit, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; [email protected] 4 Research Department, Hospital Infantil de México Federico Gómez, Mexico City 06720, Mexico; [email protected] * Correspondence: [email protected]; Tel.: +52‐55‐5623‐0700 (ext. 83210) Biology 2021, 10, 211. https://doi.org/10.3390/biology10030211 www.mdpi.com/journal/biology Biology 2021, 10, 211 2 of 4 Table S1. Search strategy. Database Search strategy Items found Date (ʺtiboloneʺ [Supplementary Concept]) AND (ʺBone MEDLINE Densityʺ[Mesh] OR ʺOsteoporosis, 135 July 17,2020 Postmenopausalʺ[Mesh]) Cochrane library tibolone AND (bone density OR osteoporosis) 126 July 17,2020 ScienceDirect: Tibolone, bone density 37 July 17,2020 Scopus Tibolone AND “bone density” 194 July 17, 2020 Epistemonikos tibolone AND (bone density OR osteoporosis) 38 July 17,2020 Lilacs Tibolona 49 July 17,2020 SciELO (tibolone) AND (bone) 4 July 17,2020 IMBIOMED Tibolona 7 July 17,2020 Medigrafic: Tibolona 6 July 17,2020 Table S2. Characteristics of the excluded studies (n = 24).
    [Show full text]
  • Gender-Affirming Hormone Therapy
    GENDER-AFFIRMING HORMONE THERAPY Julie Thompson, PA-C Medical Director of Trans Health, Fenway Health March 2020 fenwayhealth.org GOALS AND OBJECTIVES 1. Review process of initiating hormone therapy through the informed consent model 2. Provide an overview of masculinizing and feminizing hormone therapy 3. Review realistic expectations and benefits of hormone therapy vs their associated risks 4. Discuss recommendations for monitoring fenwayhealth.org PROTOCOLS AND STANDARDS OF CARE fenwayhealth.org WPATH STANDARDS OF CARE, 2011 The criteria for hormone therapy are as follows: 1. Well-documented, persistent (at least 6mo) gender dysphoria 2. Capacity to make a fully informed decision and to consent for treatment 3. Age of majority in a given country 4. If significant medical or mental health concerns are present, they must be reasonably well controlled fenwayhealth.org INFORMED CONSENT MODEL ▪ Requires healthcare provider to ▪ Effectively communicate benefits, risks and alternatives of treatment to patient ▪ Assess that the patient is able to understand and consent to the treatment ▪ Informed consent model does not preclude mental health care! ▪ Recognizes that prescribing decision ultimately rests with clinical judgment of provider working together with the patient ▪ Recognizes patient autonomy and empowers self-agency ▪ Decreases barriers to medically necessary care fenwayhealth.org INITIAL VISITS ▪ Review history of gender experience and patient’s goals ▪ Document prior hormone use ▪ Assess appropriateness for gender affirming medical
    [Show full text]
  • Raloxifene Hydrochloride
    NEW ZEALAND DATASHEET 1. EVISTA® EVISTA 60 mg tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION The active ingredient in Evista tablets is raloxifene hydrochloride. Each film coated tablet contains 60-mg raloxifene hydrochloride, which is equivalent to 56-mg raloxifene free base. For the full list of excipients, see 6.1 List of excipients. 3. PHARMACEUTICAL FORM Film coated tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications EVISTA is indicated for the prevention and treatment of osteoporosis in post-menopausal women. EVISTA is indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis. EVISTA is indicated for the reduction in the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer >1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty. 4.2 Dose and method of administration The recommended dosage is one 60-mg EVISTA tablet per day orally, which may be taken at any time of day without regard to meals. No dose adjustment is necessary for the elderly.
    [Show full text]
  • Emcyt® Estramustine Phosphate Sodium Capsules DESCRIPTION
    Emcyt® estramustine phosphate sodium capsules DESCRIPTION Estramustine phosphate sodium, an antineoplastic agent, is an off-white powder readily soluble in water. EMCYT Capsules are white and opaque, each containing estramustine phosphate sodium as the disodium salt monohydrate equivalent to 140 mg estramustine phosphate, for oral administration. Each capsule also contains magnesium stearate, silicon dioxide, sodium lauryl sulfate, and talc. Gelatin capsule shells contain the following pigment: titanium dioxide. Chemically, estramustine phosphate sodium is estra-1,3,5(10)-triene-3,17-diol(17ß)-,3­ [bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. It is also referred to as estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate. Estramustine phosphate sodium has an empiric formula of C23H30Cl2NNa2O6P•H2O, a calculated molecular weight of 582.4, and the following structural formula: CLINICAL PHARMACOLOGY Estramustine phosphate (Figure 1) is a molecule combining estradiol and nornitrogen mustard by a carbamate link. The molecule is phosphorylated to make it water soluble. 1 Estramustine phosphate taken orally is readily dephosphorylated during absorption, and the major metabolites in plasma are estramustine (Figure 2), the estrone analog (Figure 3), estradiol, and estrone. Prolonged treatment with estramustine phosphate produces elevated total plasma concentrations of estradiol that fall within ranges similar to the elevated estradiol levels found in prostatic cancer patients given conventional estradiol therapy. Estrogenic effects, as demonstrated by changes in circulating levels of steroids and pituitary hormones, are similar in patients treated with either estramustine phosphate or conventional estradiol. 2 The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.
    [Show full text]
  • Feminizing Gender-Affirming Hormone Care the Michigan Medicine Approach
    Feminizing Gender-Affirming Hormone Care The Michigan Medicine Approach Our goal is to partner with you to provide the medical care you need in affirming your gender. Our focus is on your lifelong health, safety, and individual medical and transition-related needs. The Michigan Medicine approach is based on the limited but growing medical evidence surrounding gender-affirming hormone care. Based on the available science, we believe mimicking normal physiology will provide you with the best balance of physical and emotional changes and long-term health. This philosophy aligns with current national and international medical guidelines in the care of gender diverse people. We are committed to staying up-to-date with the latest research and medical evidence to ensure you are getting the highest quality care. We know that there are competing approaches to gender-affirming care that are not based on validated scientific evidence. These approaches make scientifically unsubstantiated claims and have unknown short and long-term risks. We are happy to discuss these with you. Below are some answers to questions our patients have asked us about gender- affirming hormone care. We hope the Q&A will help you understand the medical evidence behind our approach to your gender-affirming hormone care, and how it may differ from other approaches, including the approach other well-known clinics in Southeast Michigan. Is there a benefit for monitoring both estrone (E1) and estradiol (E2) levels and aiming for a particular ratio? There are 3 naturally occurring human estrogens: estrone (E1), estradiol (E2), and estriol (E3). Your body naturally balances your estradiol and estrone ratio.
    [Show full text]
  • Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol
    [CANCER RESEARCH 39, 5155-5164, December 1979] 0008-5472/79/0039-OOOOS02.00 Binding Characteristics of a Major Protein in Rat Ventral Prostate Cytosol That Interacts with Estramustine, a Nitrogen Mustard Derivative of 17ß-Estradiol BjörnForsgren, Jan-Àke Gustafsson, Ake Pousette, and Bertil Hogberg AB Leo Research Laboratories. Pack. S-251 00 Helsingborg, Sweden [B.F.. B.H.], and Departments of Chemistry and Medical Nutrition. ¡J-ÄG.. A P.¡and Pharmacology [BH.], Karolinska Institute!. S-104 01 Stockholm 60. Sweden ABSTRACT causes atrophy of the testes and accessory sex organs; re duces the uptake of zinc by the prostate; depresses the 5a- The tissue distribution of [3H]estramustine, the dephospho- reductase, arginase, and acid phosphatase activities in the rylated metabolite of estramustine phosphate (Estracyt), in the male rat was compared to that of [3H]estradiol 30 min and 2 hr prostate; and affects lipid and carbohydrate metabolism (10, 11, 20, 29, 31 -33, 42). Although the observed effects in many following i.p. administration. In contrast to estradiol, estramus respects are similar to estrogenic effects, several experimental tine was found to be efficiently concentrated in the ventral and clinical results indicate that estramustine phosphate affects prostate gland by a soluble protein. The binding characteristics normal and neoplastic prostate tissue in a way that cannot be of this protein were studied in vitro using cytosol preparations attributed solely to its antigonadotropic or weak estrogenic of the gland. With a dextran-coated charcoal technique, the properties (15, 16, 30, 38). protein was found to bind estramustine with a broad pH opti Plym Forshell and Nilsson (35), using labeled compounds (1 mum between pH 7 and pH 8.5, with an apparent Kd of 10 to to 10 mg/kg body weight), found considerably higher levels of 30 nw, and with a binding capacity of about 5 nmol/mg cytosol radioactivity in the rat ventral prostate following i.v.
    [Show full text]
  • Editorial.Final 10/20/06 1:39 PM Page 10
    OBG_11.06_Editorial.final 10/20/06 1:39 PM Page 10 EDITORIAL Is Premarin actually a SERM? It acts like a SERM... onjugated equine estrogen Effects of tamoxifen and Premarin (Premarin) has historically been Initially, tamoxifen was characterized as an C characterized as an estrogen ago- “anti-estrogen,” but it is now recognized nist. But the report from the Women’s that tamoxifen has mixed properties. It is an Health Initiative that long-term Premarin estrogen antagonist in some tissues (breast) Robert L. Barbieri, MD Editor-in-Chief treatment is associated with a reduced risk and an estrogen agonist in other tissues of breast cancer raises the possibility that (bone). To recognize these mixed estrogen Premarin may have both estrogen agonist agonist–antagonist properties, tamoxifen is and antagonist properties. Premarin may now categorized as a SERM. Premarin and actually be better categorized as a selective tamoxifen share many similarities in their estrogen receptor modulator (SERM). effects on major clinical outcomes in post- ® Dowden Healthmenopausal Media women (Table, page 13), WHI: Premarin vs placebo including their effects on breast and In the Premarin vs placebo arm, approximately endometrial cancer, deep venous thrombo- 10,800Copyright postmenopausalFor personal women with ause prior onlysis, and osteoporotic fracture. One clinical- hysterectomy who were 50 to 79 years of age ly important divergence is that tamoxifen were randomized to Premarin 0.625 mg daily or increases and Premarin decreases vasomo- an identical-appearing placebo.1 After a mean tor symptoms. FAST TRACK follow-up of 7.1 years, the risk of invasive breast Commonly used medications that inter- In any case, cancer in the women treated with Premarin was act with the estrogen receptor can be 0.80 (95% confidence interval [CI], 0.62–1.04, arranged along a continuum from a “pure” “Use the lowest P=.09).
    [Show full text]
  • Blockade of the Stimulatory Effect of Estrogens, OH-Tamoxifen, OH
    ICANCERRESEARCH57,3494-3497.August15.19971 Blockade of the Stimulatory Effect of Estrogens, OH-Tamoxifen, OH-Toremifene, Droloxifene, and Raloxifene on Alkaline Phosphatase Activity by the Antiestrogen EM-800 in Human Endometrial Adenocarcinoma Ishikawa Cells1 Jacques Simard,2 Rocio Sanchez, Donald Poirier, Sylvain Gauthier, Shankar M. Singh, Yves Merand, Alarn Belanger, Claude Labrie, and Fernand Labile Laboratory of Molecular Endocrinology, CHUL Research Center, Quebec, Quebec, GI V 4G2, Canada ABSTRACT Because data suggest that continuous long-term tamoxifen therapy is preferable to its usual short-term use (5), and studies are already in Although temporary benefits of tamoxifen therapy are observed in up progress on the long-term administration of tamoxifen to prevent to 40% of women with breast cancer, this compound, which is known to breast cancer (13), it becomes important to make available a pure possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the antiestrogen that, due to its lack of estrogenic activity, should theo effects of the novel nonsteroidal pure antiestrogen EM-800 and related retically be more efficient than tamoxifen in treating breast cancer compounds with those of a series of antiestrogens on the estrogen-sensitive while simultaneously eliminating the risk of developing uterine car alkaline phosphatase (AP) activity in human endometrial adenocarcinoma cinoma during its long-term use. This study compares the effect of Ishikawa cells. Exposure to increasing concentrations of up to 1000 nM EM-800 or its active metabolite, EM-652, with those of OH-tamox EM-SOO or its active metabolite EM-652 alone failed to affect basal AP ifen, OH-toremifene, droloxifene, raloxifene, and !CI-182780 (14— activity.
    [Show full text]
  • Information for the User Novofem® Film-Coated Tablets Estradiol
    Package leaflet: Information for the user Novofem® film-coated tablets Estradiol/norethisterone acetate Read this entire leaflet carefully before you start taking this medicine because it contains important information for you. – Keep this leaflet. You may need to read it again. – If you have any further questions, ask your doctor or pharmacist. – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. – If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Novofem® is and what it is used for 2. What you need to know before you take Novofem® 3. How to take Novofem® 4. Possible side effects 5. How to store Novofem® 6. Contents of the pack and other information 1. What Novofem® is and what it is used for Novofem® is a sequential combined Hormone Replacement Therapy (HRT) which is taken every day without interruption. Novofem® is used in postmenopausal women with at least 6 months since their last natural period. Novofem® contains 2 hormones, an oestrogen (estradiol) and a progestagen (norethisterone acetate). The estradiol in Novofem® is identical to the estradiol produced in the ovaries of women, and is classified as a natural oestrogen. Norethisterone acetate is a synthetic progestagen, which acts in a similar manner as progesterone, another important female sex hormone. Novofem® is used for: Relief of symptoms occurring after menopause During the menopause, the amount of the oestrogen produced by a woman’s body drops.
    [Show full text]